The homeostasis of iron is of fundamental importance in the central nervous system (CNS) to ensure biological processes such as oxygen transport, mitochondrial respiration or myelin synthesis. Dyshomeostasis and accumulation of iron can be observed during aging and both are shared characteristics of several neurodegenerative diseases. Iron-mediated generation of reactive oxygen species (ROS) may lead to protein aggregation and cellular toxicity. The process of misfolding and aggregation of neuronal proteins such as α-synuclein, Tau, amyloid beta (Aβ), TDP-43 or SOD1 is a common hallmark of many neurodegenerative disorders and iron has been shown to facilitate protein aggregation. Thus, both, iron and aggregating proteins are proposed to amplify their detrimental effects in the disease state. In this review, we give an overview on effects of iron on aggregation of different proteins involved in neurodegeneration. Furthermore, we discuss the proposed mechanisms of iron-mediated toxicity and protein aggregation emphasizing the red-ox chemistry and protein-binding properties of iron. Finally, we address current therapeutic approaches harnessing iron chelation as a disease-modifying intervention in neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis.

This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

In this work we use scanning X-ray microscopy to study the structure and elemental composition of neuromelanin-positive neurons in substantia nigra tissue of Parkinson patients (PD) and controls. A total of 53 neurons were analyzed with X-ray fluorescence (XRF) and diffraction using sub-µm-focused synchrotron radiation. A statistical evaluation identified copper as the most group-discriminating element and indicated that interindividual and intraindividual variations are of great relevance in tissue measurements of diseased patients and prevent from automated group clustering. XRF analyses of two Lewy bodies (LBs) highlight a heterogeneity in elemental distributions in these LBs, whereas an innovative X-ray diffraction-based method approach was used to reveal β-sheet-rich crystalline structures in LBs. Overall, sub-µm-focus X-ray microscopy highlighted the elemental heterogeneity in PD pathology.

No abstract